Submissions for variant NM_000527.5(LDLR):c.1761C>G (p.Ser587Arg)

dbSNP: rs753430282

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238260	SCV000295643	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000775076	SCV000909178	uncertain significance	Familial hypercholesterolemia	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 33740630) and in an individual affected with coronary artery disease (PMID: 27050191). It has also been reported in a healthy control individual (PMID: 30586733). This variant has been identified in 4/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002411089	SCV002716040	uncertain significance	Cardiovascular phenotype	2022-04-13	criteria provided, single submitter	clinical testing	The p.S587R variant (also known as c.1761C>G), located in coding exon 12 of the LDLR gene, results from a C to G substitution at nucleotide position 1761. The serine at codon 587 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in a hypercholesterolemia, coronary artery cohorts; however, clinical details were limited (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Khera AV et al. J. Am. Coll. Cardiol., 2016 Jun;67:2578-89; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). This alteration was also detected in a control subject in a whole exome sequencing cohort (Khera AV et al. Circulation, 2019 03;139:1593-1602). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775076	SCV004397372	uncertain significance	Familial hypercholesterolemia	2023-06-25	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 252021). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003, 20506408, 33740630). This variant is present in population databases (rs753430282, gnomAD 0.004%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 587 of the LDLR protein (p.Ser587Arg).
All of Us Research Program, National Institutes of Health	RCV000238260	SCV004822495	uncertain significance	Hypercholesterolemia, familial, 1	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 33740630) and in an individual affected with coronary artery disease (PMID: 27050191). It has also been reported in a healthy control individual (PMID: 30586733). This variant has been identified in 4/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV004701341	SCV005201892	uncertain significance	not provided	2024-01-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16250003, 20506408, 27050191, 30586733, 27044878, 37409534, 33740630)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238260	SCV000606507	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000238260	SCV000607061	not provided	Hypercholesterolemia, familial, 1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.